Most present-day chemotherapeutic agents used in controlling eukaryotic cell proliferation (as exemplified by anticancer and antifungal agents) tend to be small molecules that are able to perform a single task relatively well, i.e., killing or arresting the proliferation of rapidly dividing cells. Unfortunately, most of these chemotherapeutics possess minimal tissue specificity and non-optimal biodistribution profiles. In addition, the use of cytotoxic or cytostatic drugs in doses sufficient to halt the growth of malignant cells represents a selection pressure that can lead to the appearance of drug resistance mechanisms.
Many plant and bacterial toxins represent successful protein designs able to penetrate mammalian cells and localize themselves into intracellular compartments. These proteins are very effective at deleting target cells or at activating non-lethal cellular processes. The understanding of how such proteins are constructed has increased dramatically in recent years.
A large number of plant and bacterial toxins can be grouped under a common theme of structural organization. They are heteromeric in nature with two or more polypeptide domains or subunits responsible for distinct functions (1). In such proteins, the two or more subunits or domains could be referred to as A and B, and the toxins as ABx toxins where x represents the number of identical or homologous B subunits in the toxin. This family of framework-related toxins includes examples such as Shiga and Shiga-like toxins, the E. coli heat-labile enterotoxins, cholera toxin, diphtheria toxin, pertussis toxin, Pseudomonas aeruginosa exotoxin A (2,3) as well as plant toxins such as ricin and abrin. Based on their ability to block protein synthesis, proteins such as Shiga and Shiga-like toxins as well as ricin, abrin, gelonin, crotin, pokeweed antiviral protein, saporin, momordin, modeccin, sarcin, diphtheria toxin and exotoxin A have been referred to as ribosome-inactivating proteins (RIP).